Aripiprazole formulations having increased injection speeds

ABSTRACT

The present invention relates to pharmaceutical compositions comprising a compound of Formula (I) that are useful for the intramuscular delivery of antipsychotic drugs using rapid injection rates.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/271,248, filed on Feb. 8, 2019 which is a continuation of U.S. patentapplication Ser. No. 16/116,652, filed on Aug. 29, 2018, now U.S. Pat.No. 10,238,651, issued on Mar. 26, 2019, which is a continuation of U.S.patent application Ser. No. 15/349,243, filed on Nov. 11, 2016, now U.S.Pat. No. 10,085,980, issued on Oct. 2, 2018, which is a continuation ofU.S. patent application Ser. No. 15/164,473, filed on May 25, 2016, nowU.S. Pat. No. 9,526,726, issued on Dec. 27, 2016, which is a divisionalof U.S. patent application Ser. No. 14/663,042, filed on Mar. 19, 2015,now U.S. Pat. No. 9,452,131, issued on Sep. 27, 2016, which claimspriority to U.S. Provisional Application Ser. No. 61/955,976 filed onMar. 20, 2014, the contents of which are hereby incorporated byreference in their entirety.

BACKGROUND

U.S. Pat. Nos. 4,734,416 and 5,006,528 disclose aripiprazole,7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinoneor 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril, as an atypical antipsychotic agent useful in the treatmentof schizophrenia, bipolar disease, depression, and other CNS disorders.Aripiprazole has the following chemical structure:

Aripiprazole is sold under the trade name ABILIFY®. It acts as adopamine D₂ partial agonist, serotonin 5-HT_(1A) receptor agonist, andis an antagonist of the serotonin 5-HT_(2A) receptor. ABILIFY® iscurrently administered orally on a once-a-day dosing schedule asABILIFY® (aripiprazole) Tablets, ABILIFY DISCMELT® (aripiprazole) OrallyDisintegrating Tablets, and ABILIFY® (aripiprazole) Oral Solution. Poorand variable patient compliance with a once-a-day dosing schedule ofpsychiatric drugs has been reported. Efforts have been made to providedrug dosage forms that may increase the compliance of patients andthereby lower the rate of relapse in the treatment of schizophrenia.

U.S. Pat. Nos. 7,807,680, 8,338,427, and 8,338,428 describe long-actingaripiprazole sterile injectable formulations. Studies on aripiprazolefree base injections showed a prolonged pharmacokinetic profile, butthere have been reports of moderate to severe tissue irritationfollowing intramuscular (IM) injection and subcutaneous (SC) injection.As such, there exists a need for improved methods of deliveringantipsychotics, such as aripiprazole, thereby improving patientcompliance and maximizing the pharmacological profile of the activeagent.

SUMMARY OF THE INVENTION

In part, the invention provided herein relates to the intramuscularadministration of pharmaceutical compositions comprising compounds ofFormula (I) to a subject in need thereof using a rapid injection rate.It was discovered that the rapid injection rate resulted in fewerinjection site failures, such as needle clogging. Surprisingly, therapid injection rate did not cause a pain intensity above a normalthreshold or any injection site reactions in the subject in needthereof. Thus, provided herein is an improved method of administeringpharmaceutical compositions comprising compounds of Formula (I), whereinthe method comprises intramuscular administration using a rapid orinstantaneous injection speed.

In one aspect, provided herein are methods of using pharmaceuticalcompositions comprising compounds of Formula (I) to treat disorders ofthe central nervous system, such as schizophrenia. In another aspect,provided herein is a method of intramuscular administration of apharmaceutical composition to a subject in need thereof, comprisingadministering to said subject a therapeutically effective amount of thecomposition at an injection rate greater than or equal to 0.3 mL/s,wherein said pharmaceutical composition comprises:

(a) 24-30 weight percent of a compound of Formula (I):

wherein n is an integer between 4 and 14;

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In another embodiment, the pharmaceutical composition comprises:

(a) about 26.6 weight percent of a compound of Formula (I);

(b) about 0.37 weight percent sorbitan laurate;

(c) about 0.15 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In another embodiment, component (a) of the pharmaceutical compositioncomprises a compound of Formula (I):

wherein n is an integer between 9 and 11.

In yet another embodiment, the pharmaceutical composition comprises:

(a) 24-30 weight percent Compound 1:

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In still another embodiment, the said pharmaceutical compositioncomprises:

(a) about 26.6 weight percent Compound 1;

(b) about 0.37 weight percent sorbitan laurate;

(c) about 0.15 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In some embodiments of the method, the injection is administered to thesubject in the dorsal gluteal muscle. In other embodiments of themethod, the injection is administered to the subject in the deltoidmuscle.

In some embodiments of the method, the needle does not experienceinjection failure due to needle clogging.

In other embodiments, the method does not elicit a pain intensity abovea normal threshold in the subject. In other embodiments, the method doesnot elicit any injection site reactions in the subject.

In another aspect, provided herein is a method of treating a disorder ofthe central nervous system in a subject in need thereof, comprisingadministering to said subject a therapeutically effective amount of thecomposition at an intravenous injection rate greater than or equal to0.3 mL/s. In one embodiment of the method, the disorder isschizophrenia.

In certain embodiments of the methods described above, the intramuscularinjection rate is greater than 0.3 mL/s.

In another aspect, provided herein is a kit useful for the treatment ofa disorder of the central nervous system, comprising a therapeuticallyeffective amount of a pharmaceutical composition and further comprisinginstructions for intramuscular injection, wherein the intramuscularinjection rate is greater than or equal to 0.3 mL/s. In one embodiment,the kit is adapted to be associated with a treatment regimen. In anotherembodiment of the kit, the intramuscular injection rate is greater than0.3 mL/s.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the occurrence of needle clogs as a function of needlegauge and user experience upon injection of a pharmaceutical compositioncomprising Compound 1 into an open cell polyurethane foam substrate.

FIGS. 2A and 2B show a summary of needle clog incidence and injectionfailure as a function of needle gauge upon injection of a pharmaceuticalcomposition comprising Compound 1 into an open cell polyurethane foamsubstrate.

FIG. 3 shows the percentage of incomplete and complete injections of apharmaceutical compostion comprising Compound 1 performed using anINSTRON® at varied injection speeds into an open cell polyurethane foamsubstrate.

FIGS. 4A and 4B show the occurrence of needle clogs as a function ofinjection speed upon injection of a pharmaceutical compositioncomprising Compound 1 into an open cell polyurethane foam substrate.

DETAILED DESCRIPTION

In part, the invention provided herein relates to the intramuscularadministration of pharmaceutical compositions comprising compounds ofFormula (I) to a subject in need thereof using a rapid injection rate.It was discovered that the rapid injection rate resulted in fewerinjection site failures, such as needle clogging. Surprisingly, therapid injection rate did not cause a pain intensity above a normalthreshold or any injection site reactions in the subject in needthereof. Thus, provided herein is an improved method of administeringpharmaceutical compositions comprising compounds of Formula (I), whereinthe method comprises intramuscular administration using a rapid orinstantaneous injection speed.

Pharmaceutical Compositions and Methods of Administering

Provided herein is an improved method of administering pharmaceuticalcompositions comprising a compound of Formula (I):

wherein n is an integer between 4 and 14;

wherein the method comprises intramuscular administration using a rapidor instantaneous injection speed.

In another embodiment, the pharmaceutical composition comprises acompound of Formula (I):

wherein n is an integer between 9 and 11.

In one aspect, provided herein is a method of intramuscularadministration of a pharmaceutical composition to a subject in needthereof, comprising administering to said subject a therapeuticallyeffective amount of the composition at an injection rate greater than orequal to 0.3 mL/s, wherein said pharmaceutical composition comprises:

(a) a compound of Formula (I):

wherein n is an integer between 4 and 14;

(b) sorbitan laurate;

(c) polysorbate 20; and

(d) an aqueous vehicle.

In one embodiment, the pharmaceutical composition comprises:

(a) a compound of Formula (I):

wherein n is an integer between 9 and 11;

(b) sorbitan laurate;

(c) polysorbate 20; and

(d) an aqueous vehicle.

Also provided herein are methods of administering pharmaceuticalcompositions, wherein the pharmaceutical compositions compriseapproximately 15-35 weight percent of a compound of Formula (I). In oneembodiment of the method, the composition comprises approximately 20-30weight percent of a compound of Formula (I). In another embodiment ofthe method, the composition comprises approximately 24-30 weight percentof a compound of Formula (I). In a particular embodiment of the method,the composition comprises approximately 26.6 weight percent of acompound of Formula (I).

In an embodiment of the method, the pharmaceutical compositioncomprises:

(a) 15-35 weight percent of a compound of Formula (I):

wherein n is an integer between 4 and 14;

(b) 0.25-0.45 weight percent sorbitan laurate;

(c) 0.2-1 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In another embodiment of the method, the pharmaceutical compositioncomprises:

(a) 15-35 weight percent of a compound of Formula (I):

wherein n is an integer between 9 and 11;

(b) 0.25-0.45 weight percent sorbitan laurate;

(c) 0.2-1 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In yet another embodiment of the method, the pharmaceutical compositioncomprises:

(a) 24-30 weight percent of a compound of Formula (I):

wherein n is an integer between 4 and 14;

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In still another embodiment of the method, the pharmaceuticalcomposition comprises:

(a) 24-30 weight percent of a compound of Formula (I):

wherein n is an integer between 9 and 11;

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In one embodiment of the method, the pharmaceutical compositioncomprises:

(a) about 26.6 weight percent of a compound of Formula (I):

wherein n is an integer between 4 and 14;

(b) about 0.37 weight percent sorbitan laurate;

(c) about 0.15 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In another embodiment of the method, the pharmaceutical compositioncomprises:

(a) about 26.6 weight percent of a compound of Formula (I):

wherein n is an integer between 9 and 11;

(b) about 0.37 weight percent sorbitan laurate;

(c) about 0.15 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In yet another embodiment of the method, the pharmaceutical compositioncomprises:

(a) 15-35 weight percent Compound 1:

(b) 0.25-0.45 weight percent sorbitan laurate;

(c) 0.2-1 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In still another embodiment of the method, the pharmaceuticalcomposition comprises:

(a) 24-30 weight percent Compound 1:

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In one embodiment of the method, the pharmaceutical compositioncomprises:

(a) about 26.6 weight percent Compound 1:

(b) about 0.37 weight percent sorbitan laurate;

(c) about 0.15 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In another embodiment of the method, the pharmaceutical composition isinjected at an injection rate greater than or equal to 0.3 mL/s.

Component (c), i.e., polysorbate 20, is sold under the trademark TWEEN®.The polysorbate can be added in an amount that reduces surface tensionof a drug product or aids in suspension stability of the drug product.

The ratio of components (b) to (c) can vary. In one embodiment, theratio of components (b) to (c) is approximately 10 to 0.5, e.g., 10 to1, e.g., 8 to 1, e.g., 5 to 2, by weight. In another embodiment, theratio of components (b) to (c) is approximately 5 to 2, by weight. Instill another embodiment, the composition comprises sorbitan monolaurate(SML) or sorbitan laurate, and polysorbate 20, wherein the ratio ofsorbitan laurate and polysorbate 20 is approximately 5 to 2, by weight.In still another embodiment, the composition comprises sorbitan laurate,and polysorbate 20, wherein the ratio of sorbitan laurate andpolysorbate 20 is approximately 3 to 1, by weight. In anotherembodiment, the composition comprises sorbitan laurate, and polysorbate20, wherein the ratio of sorbitan laurate and polysorbate 20 isapproximately 2 to 1, by weight. In yet another embodiment, thecomposition comprises sorbitan laurate, and polysorbate 20, wherein theratio of sorbitan laurate and polysorbate 20 is within the range ofapproximately 3 to 1-2 to 1, by weight. In a particular embodiment, thecomposition comprises sorbitan laurate, and polysorbate 20, wherein theratio of sorbitan laurate and polysorbate 20 is approximately a ratio of3 to a range of 1-2, by weight. In one embodiment, the compositioncomprises sorbitan laurate and polysorbate 20, wherein the ratio ofsorbitan laurate and polysorbate 20 is approximately 3 to 1.2, byweight.

As described in Table 1 below, the sorbitan laurate/polysorbate 20 ratiocan be approximately 0.625, 1, 1.25, 2, 2.5, or 5, representing a rangeof 0.625-5.

TABLE 1 Exemplary ratios of sorbitan monolaurate (SML) to polysorbate 20in example compositions of the invention. SML % Polysorbate 20%SML/Polysorbate 20 Ratio 1 0.8 1.25 0.5 0.5 1 0.5 0.2 2.5 1 0.5 2 0.50.8 0.625 1 0.2 5 0.5 0.1 5

The weight percent of components (b) and (c) can vary in thepharmaceutical compositions provided herein. In one embodiment, thecomposition comprises about 0.2-1 weight percent sorbitan laurate. Inanother embodiment, the composition comprises about 0.4-0.7 weightpercent sorbitan laurate. In still another embodiment, the compositioncomprises about 0.5 weight percent sorbitan laurate.

In another embodiment, the composition comprises about 0.25-0.45 weightpercent sorbitan laurate. In another embodiment, the compositioncomprises about 0.3-0.4 weight percent sorbitan laurate. In stillanother embodiment, the composition comprises about 0.37 weight percentsorbitan laurate.

In another embodiment, the composition comprises about 0.05-0.8 weightpercent polysorbate 20. In yet another embodiment, the compositioncomprises about 0.1-0.3 weight percent polysorbate 20. In still anotherembodiment, the composition comprises about 0.2 weight percentpolysorbate 20. In yet another embodiment, the composition comprisesabout 0.15 weight percent polysorbate 20.

The compositions provided herein can also have varying amounts of acompound of Formula (I). In one embodiment, the composition comprisesapproximately 15-35 weight percent of a compound of Formula (I). Inanother embodiment, the composition comprises approximately 24-30 weightpercent of a compound of Formula (I). In still another embodiment, thecomposition comprises approximately 20-26 weight percent of a compoundof Formula (I). In a particular embodiment, the composition comprisesapproximately 26.6 weight percent of a compound of Formula (I).

The ratio of components (a) to (b) can vary. In one embodiment, theratio of components (a) to (b) is within a range of 30 to 0.1-0.5, byweight. In another embodiment, the composition comprises a compound ofFormula (I) and sorbitan laurate, wherein the ratio of the compound ofFormula (I) to sorbitan laurate is within a range of 30 to 0.1-0.5, byweight. In yet another embodiment, the composition comprises Compound 1and sorbitan laurate, wherein the ratio of Compound 1 to sorbitanlaurate is within a range of 30 to 0.1-0.5, by weight.

In one embodiment, the ratio of components (a) to (b) is within a rangeof 30 to 0.3-0.5, by weight. In another embodiment, the compositioncomprises a compound of Formula (I) and sorbitan laurate, wherein theratio of the compound of Formula (I) to sorbitan laurate is within arange of 30 to 0.3-0.5, by weight. In yet another embodiment, thecomposition comprises Compound 1 and sorbitan laurate, wherein the ratioof Compound 1 to sorbitan laurate is within a range of 30 to 0.3-0.5, byweight.

In one embodiment, the ratio of components (a) to (b) is approximately30 to 0.5, by weight. In another embodiment, the composition comprises acompound of Formula (I) and sorbitan laurate, wherein the ratio of thecompound of Formula (I) to sorbitan laurate is approximately 30 to 0.5,by weight. In yet another embodiment, the composition comprises Compound1 and sorbitan laurate, wherein the ratio of Compound 1 to sorbitanlaurate is approximately 30 to 0.5, by weight.

In ratio of components (a) to (c) also can vary. In one embodiment, theratio of components (a) to (c) is within a range of 30 to 0.1-2, byweight. In another embodiment, the composition comprises a compound ofFormula (I) and polysorbate 20, wherein the ratio of the compound ofFormula (I) to polysorbate 20 is within a range of 30 to 0.1-2, byweight. In yet another embodiment, the composition comprises Compound 1and polysorbate 20, wherein the ratio of Compound 1 to sorbitan laurateis within a range of 30 to 0.1-2, by weight.

In one embodiment, the ratio of components (a) to (c) is within a rangeof 30 to 0.1-0.4, by weight. In another embodiment, the compositioncomprises a compound of Formula (I) and polysorbate 20, wherein theratio of the compound of Formula (I) to polysorbate 20 is within a rangeof 30 to 0.1-0.4, by weight. In yet another embodiment, the compositioncomprises Compound 1 and polysorbate 20, wherein the ratio of Compound 1to sorbitan laurate is within a range of 30 to 0.1-0.4, by weight.

In one embodiment, the ratio of components (a) and (c) is approximately30 to 0.2, by weight. In another embodiment, the composition comprises acompound of Formula (I) and sorbitan laurate, wherein the ratio of thecompound of Formula (I) to sorbitan laurate is approximately 30 to 0.2,by weight. In yet another embodiment, the composition comprises Compound1 and sorbitan laurate, wherein the ratio of Compound 1 to sorbitanlaurate is approximately 30 to 0.2, by weight.

The aqueous vehicle of the pharmaceutical compositions provided hereincan be a buffer. The buffer may be selected from a phosphate, citrate,tartrate, or acetate buffer. In a particular embodiment, the buffer is aphosphate buffer.

The pharmaceutical compositions provided herein can further compriseadditional components. For example, the pharmaceutical compositions canalso contain an aqueous vehicle, which is a vehicle that dilutes andsuspends the drug. The vehicle of interest herein is one that ispharmaceutically acceptable (safe and non-toxic for administration to ahuman) and is useful for the preparation of a reconstituted formulation.Exemplary vehicles include sterile water, sterile water for injection(WFI), bacteriostatic water for injection (BWFI), a pH buffered solution(e.g., phosphate-buffered saline), sterile saline solution, Ringer'ssolution, or dextrose solution. The buffer can be phosphate, citrate,tartrate, or acetate. In a particular embodiment, the vehicle isphosphate-buffered saline, which is a water-based salt solutioncontaining either sodium chloride or potassium chloride and eithersodium phosphate or potassium phosphate. In one embodiment, thephosphate buffer comprises isotonic saline with 5-50 mM phosphate bufferat pH 4.0-9.0, e.g., 5.0-8.0, e.g., 5.0-7.5.

Optionally, the pharmaceutical compositions can further comprise adispersant, such as, for example, carboxymethyl cellulose (CMC),carboxymethyl cellulose sodium, cross-linked sodium carboxymethylcellulose, calcium carboxymethyl cellulose, and low substitutedhydroxypropyl cellulose magnesium aluminum silicate, or a mixturethereof. In a particular embodiment, the pharmaceutical compositioncomprises carboxymethyl cellulose (CMC).

In one embodiment, the pharmaceutical composition comprises:

(a) a compound of Formula (I):

wherein n is an integer between 4 and 14;

(b) sorbitan laurate;

(c) polysorbate 20;

(d) CMC;

(e) sodium phosphate dibasic anhydrous;

(f) sodium dihydrogen phosphate monobasic dihydrate; and

(g) water for injection.

In another embodiment, the pharmaceutical composition comprises:

(a) a compound of Formula (I):

wherein n is an integer between 9 and 11;

(b) sorbitan laurate;

(c) polysorbate 20;

(d) CMC;

(e) sodium phosphate dibasic anhydrous;

(f) sodium dihydrogen phosphate monobasic dihydrate; and

(g) water for injection.

In yet another embodiment, the pharmaceutical composition comprises:

(a) Compound 1:

(b) sorbitan laurate;

(c) polysorbate 20;

(d) CMC;

(e) sodium phosphate dibasic anhydrous;

(f) sodium dihydrogen phosphate monobasic dihydrate; and

(g) water for injection.

The pharmaceutical compositions of these methods also offer minimizedexcipient levels while co-optimizing both re-suspendability andacceptable injectability, and maintain good physiochemical attributes ofthe antipsychotic agent. The compositions require reduced resuspensiontimes using, for example, hand shaking. In one embodiment, thepharmaceutical compositions can be re-suspended for injection within1-60 seconds of handshaking. Accordingly, the pharmaceuticalcompositions described herein can also be referred to as “ready to use.”

When the pharmaceutical composition is to be used as an injectablecomposition, including but not limited to injection through a needle orneedle-less injection, it can be formulated into a conventionalinjectable vehicle. Suitable vehicles include biocompatible andpharmaceutically acceptable solution and/or emulsions.

When the pharmaceutical composition is to be used as an injectablecomposition, including but not limited to injection through a needle orneedle-less injection, it can be formulated into a conventionalinjectable vehicle. Suitable vehicles include biocompatible andpharmaceutically acceptable solution and/or emulsions.

The compositions provided herein do not elicit any injection sitereactions normally associated with antipsychotic agents, such asaripiprazole, derivatives thereof, prodrugs thereof, and salts thereof.

As used herein, the term “injection site reaction” refers toinflammation or abnormal redness of the tissue and/or the skin at a siteof injection in an individual.

The modulation of the tissue response following intramusclar (IM)administration is described by the spreadability of the drug andresulting depot morphology; spreading of the drug along the fascialplanes of muscle is desirable rather than the formation of aconcentrated mass of drug in a small area.

Depot morphology resulting from IM injection of aripiprazole andcompounds of Formula (I) have been described. Injections ofslow-releasing formulations of drugs, including aripiprazole commonlyresult in the formation of “cyst-like structures”, characterized by avascularized capsule of roughly spherical shape and comprising variouscell types, with or without and a central serous fluid compartment.Tissue responses to slow-releasing formulations occur as the body mountsan immune response to clear the material from the injection site; thisreaction is commonly referred to as a foreign body response (FBR). Thespherical nature of these reactions can result in localized discomfortand pain, as the FBR increases in size compressing on nerve fibersinnervating muscle tissue and with the release of pro-inflammatorycytokines from the site.

Surprisingly, the pharmaceutical compositions provided herein do notelicit an injection site reaction following IM administration.Therefore, in one embodiment, IM adminstration of the phramaceuticalcompositions provided herein are associated with a reduced tissue andskin reaction at the site of injection. In one embodiment, the injectionsite reaction is reduced by a particular amount, e.g., about 90%, 80%,70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, etc. In another embodiment, thereis no injection site reaction following IM administration. In particularembodiments, there is no tissue or skin reaction at the site ofinjection following IM administration. In particular embodiments, IMadministration is not associated with the symptoms of the injection sitereaction, including, but not limited to: redness, tenderness, warmth,itching, pain at injection site, blistering, nodule formation, andsevere skin damage. In one embodiment, components (a), (b), and (c) ofthe pharmaceutical composition are in a container, and the aqueousvehicle is in a separate container, wherein said container is anyreceptacle and closure therefor suitable for storing, shipping,dispensing, and/or handling a pharmaceutical product. Examples of suchcontainers include, at least, for example, plastic and glass vials,ampules, pre-filled syringes and cartridges, and the like.

In certain embodiments, the pharmaceutical composition is stored in asealed (e.g., septum stoppered), colorless, glass vial.

In other embodiments, pre-filled dual-chamber syringes and/or cartridgesare utilized with the pharmaceutical compositions provided herein.Pre-filled dual-chamber syringes enable the sequential administration oftwo separate compositions with a single syringe push, thereby replacingtwo syringes with one. The benefits of a single delivery capabilityinclude increasing the speed and ease of drug administration; reducingrisk of infection by reducing the number of connections; lowering therisk of drug administration or sequence errors, and quicker delivery ofcompositions requiring combination prior to administration. Thedual-chamber syringe can accommodate lyophilized, powder, or liquidformulations in the front chamber combined with the aqueous vehicle.

Prefilled syringes can contain the exact deliverable dose of desired thepharmaceutical compositions provided herein. The prefilled syringes cancontain volumes from about 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.5 mL, 2 mL, 2.5 mL, 3 mL, 3.5 mL,4 mL, 4.5 mL, 5 mL, 5.5 mL, 6 mL, 6.5 mL, 7 mL, 7.5 mL, 8 mL, 8.5 mL, 9mL, 9.5 mL, 10 mL or more or any other volume increment thereof.

The dual syringe and/or cartridge can be side-by-side chambers withseparate syringe plungers that mix into a single chamber or linearchambers with one plunger. The dual chamber syringe and/or cartridgescan also have a stopper or connector in the middle to serve as a barrierbetween the two chambers. The stopper or connector can be removed toallow mixing or combining of the individual components in the twochambers. For example, the front chamber can accommodate components (a),(b), and (c) of the pharmaceutical compositions provided herein, and therear chamber can accommodate the aqueous vehicle. Thus, in oneembodiment, the pre-filled dual-chamber syringe contains components (a),(b), and (c) of the pharmaceutical compositions provided herein in thefront chamber and the aqueous vehicle in the rear chamber.

The pharmaceutical compositions can be formulated. The terms“pharmaceutical composition”, “formulation”, “injectable composition”,etc. are used synonymously throughout the application.

The pharmaceutical compositions described herein may also be in the formof an emulsion. The term “emulsion” as used in this specificationdenotes a two-phase system in which one phase is finely dispersed in theother phase. An emulsifier can be used in the pharmaceuticalcompositions to form the emulsion. The term emulsifier, as used by thisinvention, denotes an agent that can reduce and/or eliminate the surfaceand the interfacial tension in a two-phase system. Such an agentpossesses both hydrophilic and lipophilic groups in the emulsifieragent.

The pharmaceutical compositions described herein may also be in the formof a dispersion. As used herein, the term “dispersion” is to beunderstood as a mixture in which fine particles of one substance (e.g.,a drug) are scattered throughout another substance (e.g., a liquid).Dispersions include suspensions and colloids.

The methods of the invention include administering the compositionsdescribed herein, thereby obtaining an extended release or sustainedrelease profile in the patient. “Extended-release” or“sustained-release” includes dosage forms whose drug-releasecharacteristics of time course and/or location are chosen to accomplishtherapeutic or convenience objectives not offered by conventional dosageforms such as a solution or an immediate release dosage form. Anextended release profile includes deliveries that achieve atherapeutically effective amount of compound of Formula (I) is presentin the plasma of the individual for at least about 7 days, preferably atleast about 14 days, or more preferably at least about 21 days;alternatively, for at least 2, 3, 4, 6, or 8 weeks, or as much as threemonths.

In one embodiment, the pharmaceutical compositions can be administeredas a single or sole (undivided) dose. However, the composition is alsouseful for those individuals that require constant or chronic therapy,such as those that receive repeated doses over several hours, days,weeks, months, or more. In such dosing regimens, the method can comprisea first administration of a first extended release composition and asecond administration of a second extended release composition. Thesecond composition can be the same, substantially the same or differentas the first and can include the same active agent or a different activeagent. For example, the second composition can be administered at about7 days, or more, such as at least about 14 days, or at least about 17days, after the first administration, where the first administrationresults in the release of agent for a period of 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14 days, or more.

The injectable, pharmaceutical compositions described herein can beinjected into a patient in any number of ways. The term “injectable” asused herein refers to a composition that is suitable to be delivered toan individual in an injection, such as with an injection device,including one that employs a syringe or a cartridge, which may be housedin a manual injection device or an auto-injection device, for example.Specifically, the injectable composition is suitable for parenteraladministration. As used herein, the term “parenteral administration”refers to administration through injection or infusion. Parenteraladministration includes, but is not limited to, intravenousadministration, intradermal administration, subcutaneous administrationor intramuscular administration. The term “intravenous administration”means administration into a vein. “Intradermal administration” isinjection into the upper layer of skin (i.e., the dermis), just beneaththe epidermis. “Subcutaneous administration” refers to administrationjust below the skin. “Intramuscular administration” is the injectiondirectly into a muscle. In preferred embodiments, the injection is inthe gluteal muscle or the deltoid muscle.

Antipsychotic Agents

In one embodiment, the compound is a compound of Formula (I):

wherein n is an integer between 4 and 14.

In an embodiment, the compound is a compound of Formula (I):

wherein n is an integer between 9 and 11.

In a particular embodiment of Formula (I), n is 4 (Compound A). Inanother particular embodiment of Formula (I), n is 10 (Compound 1).Compounds A and 1 are depicted below:

Rapid Injection Speeds

The standard practice for IM adminstration of antipsychotics is toinject medications at a rate that does not exceed 1 mL per 10 seconds or0.1 mL/s [Cocoman & Murray, Journal of Psychiatric and Mental HealthNursing, 2008, Vol. 15, pp. 424-434]. Healthcare professionals suggestthat this slow, steady injection rate promotes patient comfort and helpsto avoid damage to the muscle tissue [Workman, Nuring Standard, 1999,Vol. 13, pp. 47-53].

In an effort to prevent needle clogging, manual administration of thepharmaceutical compositions provided herein was performed using fasterinjection rates. This study surprisingly revealed that the faster theuser injected the pharmaceutical compositions provided herein, the lesslikely the user was to experience a needle clog. These observations arequantitatively supported by the results from injections of thepharmaceutical compositions provided herein performed using an INSTRON®at controlled injection speeds. Indeed, as shown in FIG. 3, fasterinjection speeds are associated with a decrease in the number ofinjection clogs whereas slower injection speeds are associated with anincreased incidence of needle clogging. Furthermore, Table 6 (Example 3)reveals that increased injection speeds are associated with an increasein measured gravimetric dose delivery and, thus, better flow properties.In fact, manual administration of the pharmaceutical compositionsprovided herein revealed that slower injection rates were associatedwith an increased incidence of injection site failure due to needleclogging (see, e.g., FIGS. 3, 4A, and 4B).

As shown in FIGS. 1, 2A, and 2B, an increase in the incidence of needleclogs was observed with increased needle gauge (i.e., decreased needleinner diameter). Additionally, needle clogs were more pronounced amongfirst time or inexperienced users. Injection failures were also notedprimarily with first time users with needle gauges of 21 to 23. Noinjection failures were noted with experienced users, regardless ofneedle gauge. Given the results of the in vitro injectability assessmentof the pharmaceutical composition administered using various needlegauges, a 20 gauge needle is preferred in order to mitigate the risk ofneedle clogs.

Rapid injection rates are not typically associated with the injection ofdrugs due the increased potential for injection site reactions to occur.In fact, the prescribing information for many atypical antipsychoticsspecifies “slow injection” (see Table 2). Surprisingly, however, it hasbeen discovered that the rapid injection rate of the pharmaceuticalcompositions provided herein does not elicit injection site reactions orelevated pain intensities (above a normal threshold).

Table 2 summarizes the injection site reactions associated variousatypical antipsychotics, including Compound 1. The symptoms of theinjection site reaction include, but are not limited to: redness,tenderness, warmth, itching, pain at injection site, blistering, noduleformation, and severe skin damage. Injection site reactions and/orelevated pain levels were reported in patients upon slow injection ofABILIFY MAINTENA® (Aripiprazole Monohydrate), RISPERDAL® CONSTA®(Risperidone), and INVEGA® SUSTENNA® (Paliperidone Palmitate) incomparison with a placebo. In contrast, injection site reactions and/orelevated pain levels were reported in <1% of patients upon fastinjection of Compound 1.

TABLE 2 Summary Of Injection Site Reactions (ISRs) Associated WithAtypical Antipsychotics* Atypical Antipsychotics ABILIFY INVEGA ®MAINTENA ® RISPERDAL ® SUSTENNA ® Key product (Aripiprazole CONSTA ®(Paliperidone features Compound 1 Monohydrate) (Risperidone) Palmitate)How Supplied/ Simple Multiple step Multiple step Simple DFU,Administration DFU, PFS, DFU, vial, DFU, (it is PFS, re- requiressupplied in a vial) homogeneous suspension reconstitution, requiresre-suspension Inject inject reconstitution, in Inject slowly, rapidlyimmediately diluent supplied deep into the Inject Slowly in dose pack(in muscle. PFS) Inject entire contents of the syringe intramuscularlyinto selected gluteal or deltoid muscle Injection 441 mg: 1.6 mL 400 mg:2 mL 12.5 mg: 2 mL  39 mg: 0.25 mL volume 662 mg: 2.4 mL 300 mg: 1.5 mL  25 mg: 2 mL  78 mg: 0.50 mL 882 mg: 3.2 mL   50 mg: 2 mL 117 mg: 0.75mL 156 mg: 1.00 mL 234 mg: 1.50 mL Formulation Flocculated LyophilizedPolymer Nano-crystal suspension powder encapsulated suspensionmicropspheres ISR/Pain rate ISR: <1% Patient Patient reported: PatientExample 5 reported: ISR: no moderate reported: ISR: 6.3% or severe ISR:(no placebo) reactions were Redness, Investigator observed in anyInduration, reported: subject Swelling, >5% Redness, Investigator(occurring Induration, reported: mild twice as often Swelling, redness,swelling as placebo) pain present or induration in in 4-26% of (first tolast patients injection) (first to last injection) Needle 20 G, 1.5 in21 G, 1.5 in 20 G TW, 2 inch 22 G, 1.5 inch gauge/length & 2 in & 2 ingluteal gluteal 21 G, 1 in 21 G UTW, 1 inch 22 G, 1.5 inch >90 deltoidkg or 1 inch 23 G <90 kg deltoid *Information obtained from theprescribing information of ABILIFY MAINTENA ®, RISPERDAL ® CONSTA ®, andINVEGA ® SUSTENNA ®

Accordingly, provided herein are methods for intramuscularadministration of a pharmaceutical composition to a subject in needthereof, comprising administering to said subject a therapeuticallyeffective amount of the composition at an injection rate greater than orequal to 0.3 mL/s, wherein the pharmaceutical composition is as definedabove. In some embodiments, the injection rate is greater than 0.3 mL/s.In particular embodiments, the injection rate is greater than about 0.35mL/s, or greater than about 0.4 mL/s, greater than about 0.5 mL/s, orgreater than about 0.6 mL/s, or greater than about 0.7 mL/s, or greaterthan about 0.8 mL/s, or greater than 0.9 mL/s. In some embodiments, theinjection rate is in the range of from about 0.3 mL/s to about 1 mL/s.

In some embodiments of the method, the pharmaceutical composition isinjected using a 20 to 23 gauge needle. In other embodiments of themethod, the needle is a 20 gauge needle. In other embodiments of themethod, the needle is a 21 gauge needle. In particular embodiments, theneedle does not experience injection failure due to needle clogging.

In particular embodiments of the method, a 20 to 23 gauge needle is usedto intramuscularly administer a therapeutically effective amount of thecomposition at an injection rate greater than or equal to 0.3 mL/s,wherein the pharmaceutical composition is as defined above.

In some embodiments, the method does not elicit any injection sitereactions in the subject.

In some embodiments of the method, the injection is administered to thesubject in the dorsal gluteal muscle. In other embodiments of themethod, the injection is administered to the subject in the deltoidmuscle.

The administration by injection of a preparation comprising apharmaceutical compound is often required to be performed in arelatively short time and with a relatively high local concentration ofthe pharmaceutical agent. This practice is generally referred to in thefield as “bolus” injection. The term “bolus injection” thus identifiesthe administration at once (in general within less than few seconds) ofa pharmaceutical agent at a high concentration, differently from agradual administration of the agent (e.g. by means of intramuscular (IM)infusion).

Accordingly, in one embodiment, the method comprises intramuscularlyadministering a bolus injection of the pharmaceutical composition. Inparticular embodiments, the bolus injection is administered at a veryrapid injection rate. In some embodiments, the bolus injection isinjected with an injection rate that is greater than 0.3 mL/s. In otherembodiments, the bolus injection is injected instantaneously. Inparticular embodiments, the needle does not experience injection failuredue to needle clogging.

Lyophilization

The pharmaceutical compositions described herein can be formulated insuch a way that the active ingredient and the activeingredient-retaining substance may be dissolved in a suitable solventand subjected to lyophilization (or freeze-drying) to obtain a sterilecake of the active ingredient and the active ingredient-retainingsubstance.

In one aspect, the pharmaceutical compositions described herein arelyophilized prior to administration. Lyophilization is carried out usingtechniques common in the art [Tang et al., Pharm Res. 2004, 21, 191-200,and Chang et al., Pharm Res. 1996, 13, 243-249], and has been optimizedfor the pharmaceutical composition described herein.

A lyophilization cycle is, in one aspect, composed of three steps:freezing, primary drying, and secondary drying [A.P. Mackenzie, PhilTrans R Soc London, Ser B, Biol 1977, 278, 167]. In the freezing step,the solution is cooled to initiate ice formation. Furthermore, this stepinduces the crystallization of the bulking agent. The ice sublimes inthe primary drying stage, which is conducted by reducing chamberpressure below the vapor pressure of the ice, using a vacuum andintroducing heat to promote sublimation. Finally, adsorbed or boundwater is removed at the secondary drying stage under reduced chamberpressure and at an elevated shelf temperature. The process produces amaterial known as a lyophilized cake. Thereafter the cake can bereconstituted with either sterile water or suitable diluent forinjection.

In one aspect, provided herein is a lyophilized cake comprising apharmaceutical composition, wherein said pharmaceutical compositioncomprises:

(a) 15-35 weight percent of a compound of Formula (I);

(b) 0.25-0.45 weight percent sorbitan laurate; and

(c) 0.2-1 weight percent polysorbate 20

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In another embodiment of the lyophilized cake, the pharmaceuticalcomposition comprises:

(a) 24-30 weight percent of a compound of Formula (I);

(b) 0.3-0.4 weight percent sorbitan laurate; and

(c) 0.1-0.3 weight percent polysorbate 20

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In still another embodiment of the lyophilized cake, the pharmaceuticalcomposition comprises:

(a) about 26.6 weight percent of a compound of Formula (I);

(b) about 0.37 weight percent sorbitan laurate; and

(c) about 0.15 weight percent polysorbate 20

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In an embodiment of the lyophilized cake, the pharmaceutical compositioncomprises:

(a) 15-35 weight percent Compound 1:

(b) 0.25-0.45 weight percent sorbitan laurate; and

(c) 0.2-1 weight percent polysorbate 20

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In another embodiment of the lyophilized cake, the pharmaceuticalcomposition comprises:

(a) 24-30 weight percent Compound 1:

(b) 0.3-0.4 weight percent sorbitan laurate; and

(c) 0.1-0.3 weight percent polysorbate 20

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In still another embodiment of the lyophilized cake, the pharmaceuticalcomposition comprises:

(a) about 26.6 weight percent Compound 1:

(b) about 0.37 weight percent sorbitan laurate; and

(c) about 0.15 weight percent polysorbate 20

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In some embodiments, the lyophilized cake comprises approximately 1400mg of the pharmaceutical composition. In preferred embodiments, thecompound of Formula (I) is Compound 1.

In some embodiments, the lyophilized cake is reconstituted in an aqueousvehicle (e.g., sterile water for injection, an aqueous buffer, or salinesolution). In particular embodiments, the lyophilized cake isreconstituted in 3.0 mL of an aqueous vehicle (e.g., sterile water forinjection, an aqueous buffer, or saline solution). In particularembodiments, the lyophilized cake is reconstituted in 2.5 mL of anaqueous vehicle (e.g., sterile water for injection, an aqueous buffer,or saline solution). In particular embodiments, the lyophilized cake isreconstituted in 2.0 mL of an aqueous vehicle (e.g., sterile water forinjection, an aqueous buffer, or saline solution). In some embodiments,the lyophilized cake can be reconstituted for injection within 1-60seconds of handshaking. In preferred embodiments, the lyophilized cakecan be reconstituted for injection within 10-20 seconds of handshaking.

In one embodiment, the lyophilized cake of the pharmaceuticalcomposition is administered as part of a bolus injection.

In one aspect, provided herein is a method for preparing a lyophilizedcake of the pharmaceutical compositions provided herein.

In one embodiment, during the lyophilization process, the solvent systemused, such as by way of example only, sterile water for injection issubstantially removed by sublimation. In another embodiment, less thanabout 5% residual solvent remains after lyophilization; in otherembodiments, less than about 3% remains; in yet other embodiments, lessthan about 2% remains; in further embodiments, less than about 1% orabout 0.1% remains.

In one embodiment, the lyophilization process comprises the steps of:(1) placing the sample to be lyophilized (i.e., the pharamceuticalcomposition comprising a compound of Formula (I), sorbitan laurate, andpolysorbate 20) in a suitable vial and placing the vial into alyophilization chamber frozen in a bath until suspension was solidified;(2) cooling the lyophilization chamber and reducing the pressure of thesystem; and holding until sublimation of the solvent system issubstantially complete; and (3) slowly increasing the temperature of thelyophilization chamber to allow the samples to reach an elevated shelftemperature.

In another embodiment, the lyophilization process comprises the stepsof: (1) placing the sample to be lyophilized (i.e., the pharamceuticalcomposition comprising a compound of Formula (I), sorbitan laurate, andpolysorbate 20) in a suitable vial and placing the vial into alyophilization chamber frozen in a methanol-dry ice bath untilsuspension was solidified; (2) cooling the lyophilization chamber to−75° C. and reducing the pressure of the system to below 100 mTorr; andholding until sublimation of the solvent system is substantiallycomplete (about 72 hours); and (3) slowly increasing the temperature ofthe lyophilization chamber to allow the samples to reach a temperatureof about 20° C. to about 30° C.

In one embodiment, the lyophilized cake is in a container, and theaqueous vehicle is in a separate container, wherein said container isany receptacle and closure therefor suitable for storing, shipping,dispensing, and/or handling a pharmaceutical product. Examples of suchcontainers include, at least, for example, plastic and glass vials,ampules, pre-filled syringes and cartridges, and the like.

In some embodiments, pre-filled dual-chamber syringes and/or cartridgesare utilized with the lyophilized cakes provided herein. Thedual-chamber syringe can accommodate lyophilized, powder in the frontchamber combined with the aqueous vehicle in the rear chamber.

Prefilled syringes can contain the exact deliverable dose of desired thepharmaceutical compositions provided herein. The prefilled syringes cancontain volumes from about 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.5 mL, 2 mL, 2.5 mL, 3 mL, 3.5 mL,4 mL, 4.5 mL, 5 mL, 5.5 mL, 6 mL, 6.5 mL, 7 mL, 7.5 mL, 8 mL, 8.5 mL, 9mL, 9.5 mL, 10 mL or more or any other volume increment thereof.

The dual syringe and/or cartridge can be side-by-side chambers withseparate syringe plungers that mix into a single chamber or linearchambers with one plunger. The dual chamber syringe and/or cartridgescan also have a stopper or connector in the middle to serve as a barrierbetween the two chambers. The stopper or connector can be removed toallow mixing or combining of the compounds in the two chambers. Forexample, the front chamber can accommodate the lyophilized cake providedherein, and the rear chamber can accommodate the aqueous vehicle. Thus,in one embodiment, pre-filled dual-chamber syringe contains thelyophilized cake provided herein in the front chamber and the aqueousvehicle in the rear chamber.

Methods of Treatment

The pharmaceutical compositions of the methods provided herein can beused for the treatment of a variety of disorders in a subject in needthereof. For example, the pharmaceutical compositions described hereincan be used to treat anxiety, depression, bipolar disorder,autism-related irritability, and psychotic conditions including acutemania, schizophrenia, and schizophreniform disorder in a subject. Inanother embodiment, the pharmaceutical compositions of the methodsprovided herein can be used to treat bipolar disorder-related agitationand schizophrenic-related agitation.

In one aspect, provided herein is a method of treating a disorder of thecentral nervous system in a subject in need thereof, comprisingadministering to said subject a therapeutically amount of thecomposition at an intramuscular injection rate greater than or equal to0.3 mL/s, wherein said pharmaceutical composition comprises:

(a) 15-35 weight percent of a compound of Formula (I):

(b) 0.25-0.45 weight percent sorbitan laurate;

(c) 0.2-1 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In one embodiment of the method of treatment, the pharmaceuticalcomposition comprises:

(a) 24-30 weight percent of a compound of Formula (I);

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In another embodiment of the method of treatment, the pharmaceuticalcomposition comprises:

(a) about 26.6 weight percent of a compound of Formula (I);

(b) about 0.37 weight percent sorbitan laurate;

(c) about 0.15 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In still embodiment of the method of treatment, the pharmaceuticalcomposition comprises:

(a) 15-35 weight percent of Compound 1:

(b) 0.25-0.45 weight percent sorbitan laurate;

(c) 0.2-1 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In yet another embodiment of the method of treatment, the pharmaceuticalcomposition comprises:

(a) 24-30 weight percent of Compound 1:

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In one embodiment of the method of treatment, the pharmaceuticalcomposition comprises:

(a) about 26.6 weight percent of Compound 1:

(b) about 0.37 weight percent sorbitan laurate;

(c) about 0.15 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In an embodiment of all these methods, the method comprisesadministering to a subject in need thereof a therapeutically effectiveamount of the composition at an injection rate greater than or equal to0.3 mL/s. In particular embodiments, the injection rate is greater thanabout 0.35 mL/s, or greater than about 0.4 mL/s, greater than about 0.5mL/s, or greater than about 0.6 mL/s, or greater than about 0.7 mL/s, orgreater than about 0.8 mL/s, or greater than 0.9 mL/s. In someembodiments, the method of administration is intramuscular.

In another embodiment, the pharmaceutical composition comprises:

(a) 24-30 weight percent of a compound of Formula (I):

wherein n is an integer between 4 and 14;

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition, for use in therapy by intramuscularadministration at an injection rate greater than or equal to 0.3 mL/s.

In yet another embodiment, the pharmaceutical composition comprises:

(a) 24-30 weight percent of Compound 1:

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition, for use in therapy by intramuscularadministration at an injection rate greater than or equal to 0.3 mL/s.

In still another embodiment, the pharmaceutical composition comprises:

(e) 24-30 weight percent of a compound of Formula (I):

wherein n is an integer between 4 and 14;

(f) 0.3-0.4 weight percent sorbitan laurate;

(g) 0.1-0.3 weight percent polysorbate 20; and

(h) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition, for use in a method of treating a disorder ofthe central nervous system, wherein the composition is intramuscularlyadministered at an intramuscular injection rate greater than or equal to0.3 mL/s.

In another embodiment, the pharmaceutical composition comprises:

(a) 24-30 weight percent of Compound 1:

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition, for use in a method of treating a disorder ofthe central nervous system, wherein the composition is intramuscularlyadministered at an intramuscular injection rate greater than or equal to0.3 mL/s.

In certain embodiments of the method of treating a disorder of thecentral nervous system, the method is for maintenance treatment. Inother embodiments of the method, the method is for acute treatment.

In some embodiments of the method, the disorder of the central nervoussystem is schizophrenia, bipolar I disorder, or autistic disorder. Inone embodiment of the method, the disorder is schizophrenia. In anotherembodiment of the method, the disorder is schizophreniform disorder.

In particular embodiments of the method, the intramuscular injectionrate is greater or equal to than 0.3 mL/s. In other embodiments of themethod, the intramuscular injection rate is greater than 0.3 mL/s.

In one embodiment, a therapeutically effective amount of the agent isgiven to a subject using the pharmaceutical compositions providedherein. The term “therapeutically effective amount” is further meant todefine an amount resulting in the improvement of any parameters orclinical symptoms. The actual dose may vary with each patient and doesnot necessarily indicate a total elimination of all disease symptoms. Inthe case of antipsychotics, the management of exacerbations andmaintenance of remission of psychiatric symptoms are main goals oftherapy, and selection of the appropriate drug and dosage in aparticular disease balances these goals with the minimization of adverseevents attributable to the drug.

A therapeutically effective amount of the compound used in the treatmentdescribed herein can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of conventionaltechniques and by observing results obtained under analogouscircumstances. In determining the therapeutically effective dose, anumber of factors are considered by the attending diagnostician,including, but not limited to: the species of mammal; its size, age, andgeneral health; the specific disease involved; the degree of orinvolvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

Preferred suitable dosages for the compounds used in the treatmentdescribed herein are on the order of about 1 mg to about 600 mgpreferably about 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75, 80, 85, 90, 95, 100, 120, 140, 160, 180, 200, 220, 240, 260,280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540,560, 580 to about 600 mgs total of active agent. Dosing schedules may beadjusted to provide the optimal therapeutic response. For example,administration can be one to three times daily for a time course of oneday to several days, weeks, months, and even years, and may even be forthe life of the patient. Practically speaking, a unit dose of any givencomposition used in the treatment described herein can be administeredin a variety of dosing schedules, depending on the judgment of theclinician, needs of the patient, and so forth. The specific dosingschedule will be known by those of ordinary skill in the art or can bedetermined experimentally using routine methods. Exemplary dosingschedules include, without limitation, administration five times a day,four times a day, three times a day, twice daily, once daily, everyother day, three times weekly, twice weekly, once weekly, twice monthly,once monthly, and so forth. Unit dose preparations provided herein cancontain a compound of Formula (I) in the range of about 20 to about 900,e.g., about 60 to about 800, mgs (aripiprazole base equivalents).

Preferred amounts according to the selected mode of administration areable to be determined by one skilled in the art. Pharmaceuticalcompositions can be manufactured utilizing techniques known in the art.Typically the therapeutically effective amount of the compound will beadmixed with a pharmaceutically acceptable carrier.

Kits

Advantageously, the present invention relates to a kit comprising a unitdosage of the pharmaceutical composition of the methods disclosedherein.

In one aspect, provided herein is a kit useful for the treatment of adisorder of the central nervous system, comprising a therapeuticallyeffective amount of a pharmaceutical composition and further comprisinginstructions for intramuscular injection, wherein the intramuscularinjection rate is greater than or equal to 0.3 mL/s, wherein saidpharmaceutical composition comprises:

(a) a compound of Formula (I):

wherein n is an integer between 4 and 14;

(b) sorbitan laurate;

(c) polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In one embodiment, the pharmaceutical composition comprises:

(b) a compound of Formula (I):

wherein n is an integer between 9 and 11;

(b) sorbitan laurate;

(c) polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In another embodiment of the kit, the pharmaceutical compositioncomprises:

(a) 24-30 weight percent of a compound of Formula (I):

wherein n is an integer between 4 and 14;

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In another embodiment of the kit, the pharmaceutical compositioncomprises:

(a) 24-30 weight percent of a compound of Formula (I):

wherein n is an integer between 9 and 11;

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In still another embodiment of the kit, the pharmaceutical compositioncomprises: (a) about 26.6 weight percent a compound of Formula (I):

wherein n is an integer between 4 and 14;

(b) about 0.37 weight percent sorbitan laurate;

(c) about 0.15 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In still another embodiment of the kit, the pharmaceutical compositioncomprises:

(a) about 26.6 weight percent a compound of Formula (I):

wherein n is an integer between 9 and 11;

(b) about 0.37 weight percent sorbitan laurate;

(c) about 0.15 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In another aspect, provided herein is a kit useful for the treatment ofa disorder of the central nervous system, comprising a therapeuticallyeffective amount of a pharmaceutical composition and further comprisinginstructions for intramuscular injection, wherein the intramuscularinjection rate is greater than or equal to 0.3 mL/s, wherein saidpharmaceutical composition comprises:

(a) 15-35 weight percent of Compound 1:

(b) 0.25-0.45 weight percent sorbitan laurate;

(c) 0.2-1 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In another embodiment of the method, the pharmaceutical compositioncomprises:

(a) 24-30 weight percent Compound 1:

(b) 0.3-0.4 weight percent sorbitan laurate;

(c) 0.1-0.3 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In still another embodiment of the method, the pharmaceuticalcomposition comprises:

(a) about 26.6 weight percent of Compound 1:

(b) about 0.37 weight percent sorbitan laurate;

(c) about 0.15 weight percent polysorbate 20; and

(d) an aqueous vehicle

wherein the percentages of (a), (b), and (c) are relative to the totalweight of the composition.

In some embodiments, the kit is adapted to be associated with atreatment regimen. In preferred embodiments of the kit, the intravenousinjection rate is greater than 0.3 mL/s.

In some embodiments of the kit, the instructions are for intramuscularinjection, wherein the intramuscular injection rate is rapid orinstantaneous. In other preferred embodiments of the kit, theinstructions are for intramuscular injection, wherein the intrmuscularinjection rate is greater than 0.3 mL/s. In certain embodiments, theinjection rate is greater than about 0.35 mL/s, or greater than about0.4 mL/s, greater than about 0.5 mL/s, or greater than about 0.6 mL/s,or greater than about 0.7 mL/s, or greater than about 0.8 mL/s, orgreater than 0.7 mL/s, or greater than 0.8 mL/s, or greater than 0.9mL/s. In an embodiment, the instructions are for administeringapproximately 3.4 mL of the pharmaceutical composition within 10seconds. In another embodiment, the instructions are for administeringapproximately 1.6 mL of the pharmaceutical composition within 5 seconds.

In yet another embodiment of the kit, the instructions are foradministering the injection to the subject in the dorsal gluteal muscle.In an embodiment of the kit, the instructions are for administering theinjection to the subject in the deltoid muscle.

A “kit” as used in the instant application includes a container forcontaining the separate unit dosage forms such as a glass vial orprefilled syringe (PFS). The container can be in any conventional shapeor form as known in the art which is made of a pharmaceuticallyacceptable material, for example a paper or cardboard box, a glass orplastic bottle or jar, a re-sealable bag (for example, to hold a“refill” of tablets for placement into a different container). Thecontainer employed can depend on the exact dosage form involved, forexample a conventional cardboard box would not generally be used to holda liquid suspension. It is feasible that more than one container can beused together in a single package to market a single dosage form. Forexample, tablets may be contained in a bottle which is in turn containedwithin a box.

In some embodiments, the kit includes a 20 to 23 gauge needle. In otherembodiments of the kit, the needle is a 20 gauge needle. In otherembodiments of the kit, the needle is a 21 gauge needle.

Definitions

The terms “treat”, “treated”, “treating”, or “treatment” includes thediminishment or alleviation of at least one symptom associated or causedby the state, disorder or disease being treated. For example, treatmentcan be diminishment of one or several symptoms of a disorder or completeeradication of a disorder.

The term “weight percent” is meant to refer to the quantity by weight ofa compound and/or component in a composition as the quantity by weightof a constituent component of the composition as a percentage of theweight of the total composition. The weight percent can also becalculated by multiplying the mass fraction by 100. The “mass fraction”is the ratio of one substance of a mass m₁ to the mass of the totalcomposition m_(t).weight percent=(m ₁ /m _(t))*100

As used herein, the term “modulating” or “modulate” refers to an effectof altering a biological activity, especially a biological activityassociated with an injection site reaction.

The term “use” includes any one or more of the following embodiments ofthe invention, respectively: the use in the treatment of pain the usefor the manufacture of pharmaceutical compositions for use in thetreatment of these diseases, e.g., in the manufacture of a medicament;methods of use of compounds of the invention in the treatment of thesediseases; pharmaceutical preparations having compounds of the inventionfor the treatment of these diseases; and compounds of the invention foruse in the treatment of these diseases; as appropriate and expedient, ifnot stated otherwise.

The term “subject” is intended to include organisms, e.g., prokaryotesand eukaryotes, which are capable of suffering from or afflicted with adisease, disorder or condition associated with the activity of a proteinkinase. Examples of subjects include mammals, e.g., humans, dogs, cows,horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenicnon-human animals. In certain embodiments, the subject is a human, e.g.,a human suffering from, at risk of suffering from, or potentiallycapable of suffering from cancer, inflammation, cardiac hypertrophy, andHIV infection, and other diseases or conditions described herein (e.g.,a protein kinase-associated disorder). In another embodiment, thesubject is a cell.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “therapeutically effective amount” indicates an amountthat results in a desired pharmacological and/or physiological effectfor the condition. The effect may be prophylactic in terms of completelyor partially preventing a condition or symptom thereof and/or may betherapeutic in terms of a partial or complete cure for the conditionand/or adverse effect attributable to the condition.

As used herein, the term “pharmaceutically acceptable carrier”, andcognates thereof, refers to adjuvants, binders, diluents, etc. known tothe skilled artisan that are suitable for administration to anindividual (e.g., a mammal or non-mammal). Combinations of two or morecarriers are also contemplated in the present invention. Thepharmaceutically acceptable carrier(s) and any additional components, asdescribed herein, should be compatible for use in the intended route ofadministration (e.g., oral, parenteral) for a particular dosage form.Such suitability will be easily recognized by the skilled artisan,particularly in view of the teaching provided herein. Pharmaceuticalcompositions described herein include at least one pharmaceuticallyacceptable carrier or excipient; preferably, such compositions includeat least one carrier or excipient other than or in addition to water.

When used with respect to methods of treatment/prevention and the use ofthe compounds and pharmaceutical compositions thereof described herein,an individual “in need thereof” may be an individual who has beendiagnosed with or previously treated for the condition to be treated.With respect to prevention, the individual in need thereof may also bean individual who is at risk for a condition (e.g., a family history ofthe condition, life-style factors indicative of risk for the condition,etc.). Typically, when a step of administering a compound of theinvention is disclosed herein, the invention further contemplates a stepof identifying an individual or subject in need of the particulartreatment to be administered or having the particular condition to betreated.

In some embodiments, the individual is a mammal, including, but notlimited to, bovine, horse, feline, rabbit, canine, rodent, or primate.In some embodiments, the mammal is a primate. In some embodiments, theprimate is a human. In some embodiments, the individual is human,including adults, children and premature infants. In some embodiments,the individual is a non-mammal. In some variations, the primate is anon-human primate such as chimpanzees and other apes and monkey species.In some embodiments, the mammal is a farm animal such as cattle, horses,sheep, goats, and swine; pets such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice, and guineapigs; and the like. Examples of non-mammals include, but are not limitedto, birds, and the like. The term “individual” does not denote aparticular age or sex.

As used herein and in the appended claims, the singular forms “a”, “an”,and “the” include plural forms, unless the context clearly dictatesotherwise.

Unless defined otherwise or clearly indicated by context, all technicaland scientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs.

All relevant preferred features and embodiments apply to each of theclaims and statements of invention mentioned above.

EXEMPLIFICATION Example I—Synthesis Procedures Synthesis of Compound 1

Compound A-1: Preparation of7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one

A mixture of Aripiprazole (20 g, 45 mmol), triethylamine (1 mL, 7.1mmol), formaldehyde (37% aqueous solution, 70 mL) and dimethylformamide(200 mL) was heated to 80° C. for 20 h. The reaction mixture was cooled,diluted with ethyl acetate (400 mL) and washed with water/brine (1:1,3×500 mL). The organic phase was dried over MgSO₄, filtered andevaporated to dryness under vacuum to give hemi-aminal A-1 as a whitesolid (18.6 g, containing 25% Aripiprazole, 65% yield based on A-1).

Compound 1a:(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylacetate

A solution of Compound A-1 (50.63 g, 0.105 mol) in anhydroustetrahydrofuran (THF, 80 mL) was treated with acetic anhydride (15.3 mL,0.16 mol) and heated for 2.0 hours at 60° C. (oil-bath). To the abovesolution, triethylamine (2.0 mL, 0.014 mol) was added and stirred for 16hours at 60° C. The solvent was removed using a rotator evaporator. Tothe resulting crude mixture, ethyl acetate (150 mL) and heptane (50 mL)was added. The solution was washed with NaHCO₃ (5% aqueous solution, 250mL,). After separation of the two layers, pH of the aqueous layer wasadjusted to above 7. The aqueous layer was further extracted using theorganic mixture. The organic layer was separated and washed with 5%NaHCO₃ solution, followed by deionized water, and brine. The solutionwas dried using anhydrous MgSO₄, filtered and evaporated under vacuum.The resulting product was purified using silica gel columnchromatography using ethanol: ethyl acetate (5:95) as the eluent.Fractions containing the desired product were combined and d-tartaricacid (12.5 g dissolved in 60:5 ethanol: water) was added, resulting inthe precipitation of the desired product (48.78 g, 89% yield). ¹H NMR(CDCl3, 300 MHz) δ 1.73 (m, 2H), 1.84 (m, 2H), 2.12 (s, 3H), 2.50 (t,2H), 2.68 (m, 6H), 2.87 (dd, 2H), 3.08 (m, 4H), 3.98 (t, 2H), 5.91 (s,2H), 6.59 (m, 2H), 6.96 (dd, 1H), 7.08 (dd, 1H), 7.15 (m, 2H).

Compound 1:(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methyldodecanoate

Compound 1 was prepared in an analogous fashion to Compound 1a. Thedesired product was isolated as a crystalline solid (0.3 g, 21% yield).The molecular weight was confirmed by mass spectrometer analysis. ¹H NMR(CDCl3, 300 MHz) δ 0.87 (t, 3H), 1.24 (m, 16H), 1.62 (m, 2H), 1.83 (m,2H), 1.86 (m, 2H), 2.36 (t, 2H), 2.49 (t, 2H), 2.68 (m, 6H), 2.86 (dd,2H), 3.08 (m, 4H), 3.97 (t, 2H), 5.91 (s, 2H), 6.59 (m, 2H), 6.96 (dd,1H), 7.07 (dd, 1H), 7.14 (m, 2H).

Compound A-28:(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylbenzylcarbamate

To a solution of hemi-aminal A-1 (4 g, 8.4 mmol),4-dimethylaminopyridine (0.15 g, 1.3 mmol) and triethylamine (1.1 mL,7.5 mmol) in dichloromethane (30 mL) was added benzylisocyanate (1.03mL, 8.3 mmol) and the reaction mixture stirred for 24 hours. Thereaction mixture was then heated at 35° C. for 20 hours, cooled andwashed with water/brine (1:1, 50 mL). The organic phase was dried overMgSO₄, filtered and evaporated under vacuum. The residue was furtherpurified by chromatography on silica eluting with ethylacetate/dichloromethane/methanol (1:1:0.1) to give the desired productas an off white foam (530 mg, 14% yield). ¹H NMR (CDCl₃, 300 MHz) δ1.58-1.88 (m, 4H), 2.48 (t, 2H), 2.60-2.72 (m, 6H), 2.85 (m, 2H),3.00-3.12 (m, 4H), 3.96 (t, 2H), 4.40 (d, 2H), 5.13 (NH), 5.96 (s, 2H),6.58 (dd, 1H), 6.79 (d, 1H), 6.92-6.98 (m, 1H), 7.04 (d, 1H), 7.12-7.16(m, 1H), 7.23-7.35 (m, 6H); m/z (M⁺H) 611.12 and 613.10.

Compound A:(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylhexanoate

Compound A was prepared in an analogous fashion to Compound A-28. Thedesired product was isolated as a yellow solid (3.69 g, 87% yield). ¹HNMR (CDCl₃, 300 MHz) δ 0.78 (t, 3H), 1.11-1.28 (m, 4H), 1.40-1.78 (m,6H), 2.20-2.40 (m, 4H), 2.40-2.60 (m, 6H), 2.73-2.81 (m, 2H), 2.85-3.00(m, 4H), 3.88-4.00 (m, 2H), 5.75-5.83 (m, 2H), 6.55-6.62 (m, 2H),7.03-7.12 (m, 2H), 7.20-7.26 (m, 2H). m/z (M^(P)H) 576.4 and 578.4.

Example II—Exemplary Formulations

TABLE 3 Example formulation of the invention. Amount Per FormulationDose (%w/w) Compound 1 26.6  Sorbitan monolaurate 0.37 Polysorbate 200.15 Sodium Chloride 0.59 CMC NA Sodium Phosphate Dibasic 0.06 AnhydrousSodium Dihydrogen Phosphate 0.05 Monobasic Dihydrate Water for InjectionQS to 100 pH range: 5.0-7.4

Example III: In Vitro Assessments of Compound 1 PFS Product Performancewhen Administered Using Various Needle Gauges and at Varied InjectionSpeeds

An in vitro assessment was carried out with an pre-filled syringe (PFS)containing the formulation of Example II. Product performance wasassessed by measuring the amount of drug product that was injected afterresuspension into a foam resistance model (gravimetric dose deliverywith applied resistance). The drug product was injected into open cell(250 to 300 μm pore size) polyurethane foam and the gravimetricdelivered dose is measured. The injection was performed manually byeither users who were categorized as experienced or inexperienced or byan INSTRON® universal testing machine at constant injection speed(INSTRON®, Norwood, Mass.). An experienced user is defined as those thathave conducted injections of the Compound 1 drug product previously,such as, physicians or lab analysts. An inexperienced user is defined aspersonnel that are not lab analysts or those that have never conductedinjections of the Compound 1 drug product. Mean inner diameters forneedle gauges used in this experiment are listed in Table 4.

TABLE 4 Terumo Needle Gauge and Mean Internal Needle Diameter NeedleNeedle Internal Needle Gauge Diameter (μm) 23 405 22 485 21 575 20 660Manual In Vitro Assessment of PFS Injectabilty:

A total of 1460 injections by 44 users were completed according to thefollowing primary steps:

1. Resuspend the syringe contents by shaking vigorously for ˜30 seconds

2. Attach needle to the syringe

3. Prime the syringe by bringing it into an upright position, tap thesyringe to bring air to the top and then carefully depress the plungerrod until ˜1-2 drops of suspension are released

4. Inject the full contents into foam in a rapid and continuous manner(<10 seconds)

5. If a clog occurs, replace the needle and attempt to complete theinjection. If a second clog occurs, continue to the next step

6. Record the weight of the suspension following completion of theinjection to determine gravimetric dose delivery.

Each user was given a spare needle in the event of a needle clog. Eachneedle clog was recorded as were injection failures (defined byinability to deliver entire contents of a syringe following use of thespare (2nd) needle).

In Vitro Assessment of PFS Injectabilty using an INSTRON® UniversalMaterials Tester in Compression Mode at Varied Injection Speeds:

Ten injections were performed at each injection speed according to thefollowing primary steps:

1. Resuspend the syringe contents on a Burrel wrist action shaker for 30Seconds.

2. Prime the syringe by bringing it into an upright position, tap thesyringe to bring air to the top and then carefully depress the plungerrod until ˜1-2 drops of suspension are released.

3. Place the syringe in the INSTRON® syringe test fixture.

4. Inject the contents of the syringe into the foam at constantinjection speed to max force of 40 N.

5. Record the weight following completion of the injection to determinegravimetric dose delivery.

One needle replacement was allowed per syringe tested. Each needle clogwas recorded as were injection failures (defined by inability to deliverentire contents of a syringe following use of the spare (2nd) needle).

Manual In Vitro Assessment of Compound 1 PFS Injectability

A summary of needle clogs as a function of needle gauge and userexperience is shown in FIG. 1. A summary of needle clog incidence andinjection failures as a function of needle gauge and user experience isshown in FIGS. 2A and 2B. Measured gravimetric dose delivery wascompared to the expected dose delivery of the high dose. Gravimetricdose delivery results and number of injections that delivered less than75% of expected as a function of needle gauge for all users aresummarized in Table 5.

TABLE 5 In Vitro Assessment of Injectability by Gravimetric DoseDelivery Total Number (%) of Injections Gravimetric Dose Needle Numberof less than 75% of expected Delivery (g), Gauge Injections dosedelivery Average ± SD 23 390 4 (1.0%) 3.41 ± 0.15 22 350 3 (0.9%) 3.41 ±0.19 21 370 1 (0.3%) 3.42 ± 0.11 20 350 0 (0%)  3.41 ± 0.05

In Vitro Assessment of PFS Injectabilty using an INSTRON®

A summary of incomplete and complete injections performed using theINSTRON® at varied injection speeds is shown in FIG. 3. A summary of theresultant gravimetric dose delivery results is shown in Table 6.

TABLE 6 Gravimetric Dose Delivery Results From Injections PerformedUsing an INSTRON ® at Varied Injection Speeds Injection Gravimetric DoseDelivery(g), Speed Average ± SD 180 0.99 ± 0.37 225 2.26 ± 0.86 260 2.81± 0.51 300 3.23 ± 0.12 360 3.27 ± 0.05 450 3.30 ± 0.03

Example IV—Exemplary Suspension Lyophilization for Increased Dose

Suspension

Lyophilization:

-   -   1. Re-suspended Compound 1 injectable suspension (i.e., the        formulation of Example II) was pooled into BD 50 mL        polypropylene conical tube. Total twenty PFS were pooled into        four conical tubes.    -   2. Conical tubes were frozen in a methanol-dry ice bath until        suspension was solidified. Tubes were allowed to freeze further        15 min to ensure complete freezing of a suspension.    -   3. Lyophilizer condenser was cooled to −75° C. and vacuum was        maintained below 100 mTorr.    -   4. Frozen tubes were transferred into lyophilizer vacuum flask.        Vacuum flask was attached to bulk lyophilizer port and        immediately vacuum was applied.    -   5. Lyophilization was continued for about 72 hours.    -   6. After 72 hours vacuum was released and vacuum flask was        removed from the lyophilizer.    -   7. Conical tubes containing lyophilized product were capped at        an ambient condition and tapped on a hard surface to break the        cake.        Injectability Evaluation:    -   1. Lyophilized product was filled into cyclic olefin copolymer        (COC) PFS barrel or glass vial.    -   2. Required volume of water for injection was added.    -   3. Lyophilized product was reconstituted and injected into a        foam (model: injectability with resistance) following directions        for use (DFU) for Compound 1 injectable suspension.    -   4. Test parameters and observations were recorded in Table 7.

TABLE 7 Injectability Evaluation Container/ Mass Reconstitution Closure(mg) Volume (mL) Observations 5 mL COC 900 3.0 Product was acceptablyPFS reconstituted within 10-20 sec shaking Rapid and continuousinjection resulted in complete injection into a foam 5 mL COC 900 3.0Product was acceptably PFS reconstituted within 10-20 sec shaking Rapidand continuous injection resulted in complete injection into a foam 5 mLCOC 900 2.0 Product was acceptably PFS reconstituted within 10-20 secshaking Slow injection resulted in needle clog into a foam Clog wasremoved and complete injection was performed rapidly into a foam 5 mLCOC 900 2.0 Product was acceptably PFS reconstituted within 10-20 secshaking Rapid and continuous injection resulted in complete injectioninto a foam 10 mL Glass 1400 2.5 Product was acceptably Vialsreconstituted within 10-20 sec shaking Rapid and continuous injectionresulted in complete injection into a foam 10 mL Glass 1400 2.5 Productwas acceptably Vials reconstituted within 10-20 sec shaking Rapid andcontinuous injection resulted in complete injection into a foam 10 mLGlass 1400 2.5 Product was acceptably Vials reconstituted within 10-20sec shaking Rapid and continuous injection resulted in completeinjection into a foam

Example V. Rapid Intramuscular (IM) Injection of Compound 1 on Pain andInjection Site Reactions (IRS)

Injection site reactions and pain upon IM injection of Compound 1 are apotential safety concern. A Phase 3, multicenter, extension study wasconducted in 81 sites to assess the effect of rapid IM injections ofCompound 1 on human patients diagnosed with stable schizophrenia.Briefly, 332 subjects enrolled in the study were assigned PFS. Compound1 is formulated as a pre-filled syringe (PFS) of an extended releaseaqueous suspension of a therapeutically effective amount of Compound 1.An injection volume of 3.4 mL or 1.6 mL of the aqueous suspension wasadministered according to protocol I at a rate of less than 10 secondsby inserting the 20 gauge needle in the gluteal muscle. ISRs upon IMinjection of Compound 1 were assessed at each visit. Over 5000injections of Compound 1 have been administered intramuscularly with anISR rate of less than 1%.

Protocol I

-   1. TAP the pre-filled syringe at least 10 times to dislodge any    material that may have settled.-   2. SHAKE the pre-filled syringe vigorously for a minimum of 30    seconds to ensure a uniform suspension.-   If the syringe is not used within 15 minutes, re-suspend by shaking    vigorously for 30 seconds.-   3. SELECT the injection needle. For patients with a larger amount of    subcutaneous tissue overlying the gluteal muscle, use the longer of    the needles provided to ensure the injectate reaches the    intramuscular mass. Both the 1½ and 2 inch administration needles    are provided to accommodate varying patient body habitus.-   4. ATTACH the injection needle. Remove the syringe tip cap with an    easy counter-clockwise twisting motion. Attach the appropriate    needle with an easy clockwise twisting motion. Remove the needle    sheath with straight, firm pull.-   5. PRIME the syringe to remove air. Bring the syringe into upright    position and tap the syringe to bring air to the top. Remove air by    depressing the plunger rod. A few drops of suspension will be    released.-   6. ADMINISTER the entire contents intramuscularly. Inject in a rapid    and continuous manner (less than 10 seconds). DO NOT inject    intravenously or subcutaneously.-   Prior to injection aspirate for blood. [If blood aspirates, do not    inject. Replace with new needle (Steps 3 & 4) and administer into an    adjacent site in the same gluteal muscle (Steps 5 & 6).]-   If you are unable to complete the injection, replace with new needle    (Steps 3 & 4) and readminister into an adjacent site in the same    gluteal muscle (Steps 5 & 6).-   7. DISPOSE of the needle. Cover the needle by pressing the safety    device. Dispose of used and unused items in a proper waste    container.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

The invention claimed is:
 1. A method of treating schizophrenia in asubject in need thereof, comprising intramuscularly administering tosaid subject a therapeutically amount of the composition at a rapid andcontinuous intramuscular injection rate, wherein said pharmaceuticalcomposition comprises: (a) 24-30 weight percent of compound 1:

(b) 0.3-0.4 weight percent sorbitan laurate; (c) 0.1-0.3 weight percentpolysorbate 20; and (d) an aqueous vehicle wherein the percentages of(a), (b), and (c) are relative to the total weight of the composition;and wherein the pharmaceutical composition has a total injection volumefrom about 1.5 mL to 4.0 mL.
 2. The method of claim 1, wherein theintramuscular injection rate is selected from the group consisting of0.3 mL/s, 0.35 mL/s, 0.4 mL/s, 0.5 mL/s, 0.6 mL/s, 0.7 mL/s, 0.8 mL/s,and 0.9 mL/s.
 3. The method of claim 1, wherein the total volume of thepharmaceutical composition is approximately 3.2 mL, 2.4 mL, or 1.6 mL.4. The method of claim 3, wherein approximately 3.2 mL of thepharmaceutical composition is injected within 10 seconds.
 5. The methodof claim 3, approximately 2.4 mL of the pharmaceutical composition isinjected within 8 seconds.
 6. The method of claim 3, whereinapproximately 1.6 mL of the pharmaceutical composition is injectedwithin 5 seconds.
 7. A kit useful for the treatment of schizophrenia,wherein the kit comprises a therapeutically effective amount of apharmaceutical composition and further comprises instructions forintramuscular injection, wherein the instructions specify a rapid andcontinuous intramuscular injection rate, wherein said pharmaceuticalcomposition comprises: (e) 24-30 weight percent Compound 1:

(f) 0.3-0.4 weight percent sorbitan laurate; (g) 0.1-0.3 weight percentpolysorbate 20; and (h) an aqueous vehicle wherein the percentages of(a), (b), and (c) are relative to the total weight of the composition;and wherein the pharmaceutical composition has a total injection volumefrom about 1.5 mL to 4.0 mL.
 8. The kit according to claim 7, whereinthe kit is adapted to be associated with a treatment regimen.
 9. The kitaccording to claim 7, wherein the intramuscular injection rate isselected from the group consisting of 0.3 mL/s, 0.35 mL/s, 0.4 mL/s, 0.5mL/s, 0.6 mL/s, 0.7 mL/s, 0.8 mL/s, and 0.9 mL/s.
 10. The kit of claim7, wherein the total volume of the pharmaceutical composition isapproximately 3.2 mL, 2.4 mL, or 1.6 mL.
 11. The kit of claim 10,wherein approximately 3.2 mL of the pharmaceutical composition isinjected within 10 seconds.
 12. The kit of claim 10, whereinapproximately 2.4 mL of the pharmaceutical composition is injectedwithin 8 seconds.
 13. The kit of claim 10, wherein approximately 1.6 mLof the pharmaceutical composition is injected within 5 seconds.